Abstract
Mouse N-ethyl-N-nitrosourea (ENU) mutagenesis has generated many useful animal models for human diseases. Here we describe the identification of a novel ENU-induced mouse mutant strain Turner (Tur) that displays circling and headtossing behavior and progressive hearing loss. Tur/Tur homozygous animals lack Preyer and righting reflexes and display severe headtossing and reaching response defect. We mapped the Tur mutation to a critical region of 11 cM on chromosome 9 that includes myosin VI. Direct sequence analysis revealed a c.820A>T substitution in exon 8 of the Myo6 gene that changes amino acid Asn200 to Ile (p.N200I) in the motor domain. Analysis of inner ear hair cells by immunohistochemistry, scanning electron microscopy and histology revealed degeneration of hair cells in the inner ear and structural malformation of the stereocilia in the cochlea of Turner homozygous mutant mice. Our data indicate that this novel mouse strain provides a useful model for future studies on the function of myosin VI in mammalian auditory and non-auditory systems and in human syndromes.
Highlights
Deafness is the most common sensory disorder in humans, produced primarily by damage to the inner ear sensory hair cells and their associated spiral ganglion neurons
Turner is a dominant mutation causing vestibular dysfunction and hearing loss The Turner founder was initially discovered in a large-scale screen of ENU-mutagenized mouse strains because of its mild headtossing and circling behavior, which was shown to have a dominant inheritance by outcrossing the founder C57BL/6J-Tur/+ to wild-type C3HeB/FeJ mice
We have identified a c.820A>T in Myo6 responsible for inner ear defects such as headtossing, circling, and deafness displayed by our ENU mutant mouse strain Turner
Summary
Deafness is the most common sensory disorder in humans, produced primarily by damage to the inner ear sensory hair cells and their associated spiral ganglion neurons. Over the past several decades, large numbers of new mouse mutants with deafness or vestibular dysfunction have been generated through large-scale ENU and other mutagenesis programs. The Myo gene was first reported to be mutated in Snell’s waltzer mice that exhibited circling and headtossing behavior and deafness due to loss of hair cells [2]. It encodes a 1265 amino acid protein (140 kD) that consists of an N-terminal motor domain involved in actin-binding and movement, a calmodulin interacting neck domain and a C-terminal tail domain that often connects to various cargo associated
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